The long-term objective of both the proposal and candidate is to better understand the interaction of malignancies and tumor specific T cell reconstitution in the setting of hematopoietic transplantation, such that improved immunotherapeutic strategies can be developed. This proposal describes a 5-year mentored training program for the principal investigator, who has completed residency training in both internal medicine and pediatrics and fellowship training in hematology/oncology and bone marrow transplantation. The applicant now seeks to acquire additional training and expanded research skills with the goal of preparation for independence as a physician scientist. This program will promote the development of skills in hematopoietic stem cell biology as applied towards transplantation immunology and development of a novel strategy of hematopoietic stem cell (HSC) derived immunotherapy. Dr. Irving Weissman, a recognized leader in the field of stem cell biology who has trained numerous postdoctoral students and graduate students will mentor the principal investigator's scientific development with additional guidance provided by a selected advisory committee. The long range goal of this project is to address the question of whether hematopoietic stem cells carrying genes encoding anti-tumor T cell receptors (TCR) can generate tumor reactive T cells and generate a directed graft versus malignacy effect without graft versus host disease (GVHD). Such antigen specific TCR transduced HSC could, with a single inoculum of modified stem cells provide cancer patients with a continuously renewing and expanding pure population of tumor reactive T cells. The central hypothesis of this work is that stem cell derived immunotherapy can provide a powerful, long acting and tumor specific immune response following transplantation. To explore proof of principle of such a strategy we propose to (1) Develop a murine model of Acute Myeloid Leukemia (AMI), modified to express 2 model tumor/leukemia associated antigens, (2) Determine the ability of HSC and common lymphocyte progenitors (CLP) derived from TCR transgenic mice which express TCR specific to model antigens to engraft into non-transgenic recipients and generate Class I or Class II restricted antigen-specific T cells; (3) Define the reactivity of naive and activated TCR transgenic donor derived T-cells in-vitro as well as following adoptive transfer into mice bearing AML expressing the target model tumor antigens; (4) Determine the ability of transplanted TCR-transgenic HSC to generate tumor antigen specific T-cells and affect tumor specific GVL in recipients bearing AML at the time of and following transplantation. Proof of principle of such a stem cell-derived immunotherapy strategy could lead to translation to the clinic, where patients receiving ablative and non-myeloablative transplants could engender a specific GVL response without GVHD, thereby effecting long term cure and prevention of relapse from minimal residual disease present at the time of transplant.